Methods and systems for identifying or treating central nervous systems disease

Abstract

Systems and methods for the identification of auto-antibodies associated with central nervous system or psychiatric disease or disorders. Also disclosed herein are methods of treating central nervous system or psychiatric disease or disorders associated with auto-antibodies.

1 . A method for the treatment or improvement of a psychiatric or central nervous system disease or disorder, wherein the psychiatric or central nervous system disease or disorder is not encephalitis, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen binding fragment thereof that binds to an N-methyl-D-aspartate (NMDA) receptor comprising a heavy chain variable region and a light chain variable region, the heavy and light chain variable region comprising:
 (a) a heavy chain CDR1 as set forth in SEQ ID NO: 11, a heavy chain CDR2 as set forth in SEQ ID NO: 12, a heavy chain CDR3 as set forth in SEQ ID NO: 13, a light chain CDR1 as set forth in SEQ ID NO: 14, a light chain CDR2 as set forth in SEQ ID NO:15, and a light chain CDR3 as set forth in SEQ ID NO:16;   (b) a heavy chain CDR1 as set forth in SEQ ID NO: 17, a heavy chain CDR2 as set forth in SEQ ID NO: 18, a heavy chain CDR3 as set forth in SEQ ID NO: 19, a light chain CDR1 as set forth in SEQ ID NO: 20, a light chain CDR2 as set forth in SEQ ID NO:21, and a light chain CDR3 as set forth in SEQ ID NO:22;   (c) a heavy chain CDR1 as set forth in SEQ ID NO:23, a heavy chain CDR2 as set forth in SEQ ID NO: 24, a heavy chain CDR3 as set forth in SEQ ID NO: 25, a light chain CDR1 as set forth in SEQ ID NO: 26, a light chain CDR2 as set forth in SEQ ID NO:27, and a light chain CDR3 as set forth in SEQ ID NO:28;   (d) a heavy chain CDR1 as set forth in SEQ ID NO: 29, a heavy chain CDR2 as set forth in SEQ ID NO: 30, a heavy chain CDR3 as set forth in SEQ ID NO: 31, a light chain CDR1 as set forth in SEQ ID NO: 32, a light chain CDR2 as set forth in SEQ ID NO:33, and a light chain CDR3 as set forth in SEQ ID NO:34;   or   (e) a heavy chain CDR1 as set forth in SEQ ID NO: 35, a heavy chain CDR2 as set forth in SEQ ID NO: 36, a heavy chain CDR3 as set forth in SEQ ID NO: 37, a light chain CDR1 as set forth in SEQ ID NO: 38, a light chain CDR2 as set forth in SEQ ID NO:39, and a light chain CDR3 as set forth in SEQ ID NO:40.   
     
     
         2 . The method of  claim 1 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 80% sequence identity to any one of SEQ ID NOs: 1, 3, 5, 7, or 9, and the light chain variable region comprises an amino acid sequence that has at least 80% sequence identity to any one of SEQ ID NOs: 2, 4, 6, 8, or 10. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the heavy chain variable region comprises an amino acid sequence identical to any one of SEQ ID NOs: 1, 3, 5, 7, or 9, and the light chain variable region comprises an amino acid sequence identical to any one of SEQ ID NOs: 2, 4, 6, 8, or 10. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the psychiatric or central nervous system disease or disorder is schizophrenia, psychosis, bipolar disorder, depression, epilepsy, or dementia. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the antibody or antigen binding fragment thereof binds an (NR1) subunit of the NMDA receptor. 
     
     
         13 . The method of  claim 1 , wherein the antibody or antigen binding fragment thereof comprises a Fab, Fab 2 , or an scFv. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A method for identifying an antibody or antigen binding fragment thereof for use in treatment of a psychiatric or central nervous system disease or disorder, the method comprising identifying said antibody or antigen binding fragment thereof that binds specifically to an epitope LQNRKLV (SEQ ID NO: 41) of a NR1 subunit of a NMDA receptor. 
     
     
         17 . The method of  claim 16 , wherein said antibody or antigen binding fragment thereof inhibits binding of an autoantibody that binds to said NMDA receptor. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 16 , wherein the antibody or antigen binding fragment thereof is human or humanized. 
     
     
         21 - 27 . (canceled) 
     
     
         28 . A method for identifying a subject as having a risk of autoantibody associated disease comprising:
 (a) obtaining a biological sample from said subject;   (b) assaying said biological sample for antibodies that bind to the amino acid sequence LQNRKLV (SEQ ID NO: 41); and   (c) optionally, outputting a report or identifying said subject as being at high risk or low risk for said autoantibody associated disease.   
     
     
         29 . The method of  claim 28 , wherein said biological sample comprises blood, sweat, saliva, cerebrospinal fluid (CSF), amniotic fluid, or mucus. 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 28 , further comprising treating said subject for said autoantibody associated disease. 
     
     
         33 - 37 . (canceled) 
     
     
         38 . The method of  claim 32 , wherein the antibody or antigen binding fragment thereof binds NMDAR1. 
     
     
         39 . (canceled) 
     
     
         40 . The method of claim  37 , wherein the antibody or antigen binding fragment thereof binds at least one amino acid of the sequence LQNRKLV (SEQ ID NO: 41). 
     
     
         41 . The method of  claim 28 , wherein the autoantibody associated disease comprises a psychiatric or central nervous system disease or disorder. 
     
     
         42 . The method of  claim 28 , wherein the autoantibody associated disease comprises schizophrenia, psychosis, bipolar disorder, depression, epilepsy, or dementia. 
     
     
         43 . The method of  claim 28 , wherein the autoantibody associated disease comprises encephalitis. 
     
     
         44 . The method of  claim 32 , wherein the treating comprises administering a therapeutically effective amount of an antibody that binds the NR1 subunit of NMDAR1. 
     
     
         45 . The method of  claim 38 , wherein the antibody that binds NMDAR1 comprises a heavy chain variable region and a light chain variable region, the heavy and light chain variable region comprising:
 (a) a heavy chain CDR1 as set forth in SEQ ID NO: 11, a heavy chain CDR2 as set forth in SEQ ID NO: 12, a heavy chain CDR3 as set forth in SEQ ID NO: 13, a light chain CDR1 as set forth in SEQ ID NO: 14, a light chain CDR2 as set forth in SEQ ID NO:15, and a light chain CDR3 as set forth in SEQ ID NO:16;   (b) a heavy chain CDR1 as set forth in SEQ ID NO: 17, a heavy chain CDR2 as set forth in SEQ ID NO: 18, a heavy chain CDR3 as set forth in SEQ ID NO: 19, a light chain CDR1 as set forth in SEQ ID NO: 20, a light chain CDR2 as set forth in SEQ ID NO:21, and a light chain CDR3 as set forth in SEQ ID NO:22;   (c) a heavy chain CDR1 as set forth in SEQ ID NO:23, a heavy chain CDR2 as set forth in SEQ ID NO: 24, a heavy chain CDR3 as set forth in SEQ ID NO: 25, a light chain CDR1 as set forth in SEQ ID NO: 26, a light chain CDR2 as set forth in SEQ ID NO:27, and a light chain CDR3 as set forth in SEQ ID NO:28;   (d) a heavy chain CDR1 as set forth in SEQ ID NO: 29, a heavy chain CDR2 as set forth in SEQ ID NO: 30, a heavy chain CDR3 as set forth in SEQ ID NO: 31, a light chain CDR1 as set forth in SEQ ID NO: 32, a light chain CDR2 as set forth in SEQ ID NO:33, and a light chain CDR3 as set forth in SEQ ID NO:34; or   (e) a heavy chain CDR1 as set forth in SEQ ID NO: 35, a heavy chain CDR2 as set forth in SEQ ID NO: 36, a heavy chain CDR3 as set forth in SEQ ID NO: 37, a light chain CDR1 as set forth in SEQ ID NO: 38, a light chain CDR2 as set forth in SEQ ID NO:39, and a light chain CDR3 as set forth in SEQ ID NO:40.   
     
     
         46 . The method of  claim 45 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 80% sequence identity to any one of SEQ ID NOs: 1, 3, 5, 7, or 9, and the light chain variable region comprises an amino acid sequence that has at least 80% sequence identity to any one of SEQ ID NOs: 2, 4, 6, 8, or 10.